Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.

Abstract

Molecular/theoretical modeling studies have revealed that thyroid hormones and toxic chlorinated aromatic hydrocarbons of environmental significance (for which dioxin or TCDD is the prototype) have similar structural properties that could be important in molecular recognition in biochemical systems. These molecular properties include a somewhat rigid, sterically accessible and polarizable aromatic ring and size-limited, hydrophobic lateral substituents, usually contained in opposite adjoining rings of a diphenyl compound. These molecular properties define the primary binding groups thought to be important in molecular recognition of both types of structures in biochemical systems. Similar molecular reactivities are supported by the demonstration of effective specific binding of thyroid hormones and chlorinated aromatic hydrocarbons with four different proteins, enzymes, or receptor preparations that are known or suspected to be involved in the expression of thyroid hormone activity. These binding interactions represent both aromatic-aromatic (stacking) and molecular cleft-type recognition processes. A multiple protein or multifunctional receptor-ligand binding mechanism model is proposed as a way of visualizing the details and pbssible role of both the stacking and cleft type molecular recognition factors in the expression of biological activity. The model suggests a means by which hormone-responsive effector-linked sites (possible protein-protein-DNA complexes) can maintain highly structurally specific control of hormone action. Finally, the model also provides a theoretical basis for the design and conduct of further biological experimentation on the molecular mechanism(s) of action of toxic chlorinated aromatic hydrocarbons and thyroid hormones.

Dioxin effects on neonatal and infant thyroid function: routes of perinatal exposure, mechanisms of action and evidence from epidemiology studies

“…The observation of structure similarities between TCDD and thyroid hormones prompted structureactivity relationship (Cheek et al 1999;McKinney and Waller 1998) and in-vitro competitive binding studies (Cheek et al 1999;McKinney 1989) that confirmed that TCDD properties resemble those of thyroid hormones triiodothyroxine (T 3 ) and thyroxine (T 4 ) (Porterfield 2000). However, affinity of dioxin-like compounds is low for thyroid receptor and elevated for serum transport proteins (Cheek et al 1999).…”

“…A variety of chemicals have been identified that may interfere with synthesis, secretion, transport, metabolism, or receptorial actions of endogenous hormones. Analysis of TCDD chemical structure reveals that TCDD bears a structural resemblance to the natural thyroid hormones (Baccarelli et al 2000;McKinney 1989). Proteins that bind thyroid hormones in vivo may also bind to TCDD and other structure-related compounds.…”

“…2). Qualitative structure requirements for high toxicity include planarity or coplanarity of structure in a shape approximating a rectangle and a sufficient degree of halogenation concentrated in lateral positions (McKinney 1989).…”

Endocrine Disruptors as Pollutants in Marine Ecosystem: A Case Study in Egypt

“…Prenatal exposure to PCBs/dioxins in laboratory animals induces a decrease in plasma T4 levels without significantly altering the growth [57], and T3 levels remain within the normal range [58], indicating that the toxicity of these chemicals does not manifest by altering blood TH levels. On the other hand, because the molecular structures of PCBs/dioxins are similar to those of TH, these chemicals are considered to act via TH receptors (TRs) [59]. Furthermore, these compounds can be transferred across the blood-brain barrier and accumulate in the brain [60].…”

Long-term carcinogenesis studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins

“…TCDD does not bind to the different receptor proteins involved in this system. However, interaction with a hypothetical thyroxine receptor has been proposed as a mechanism for the thyroxine-like effects produced by TCDD in some systems (McKinney et al 1985(McKinney et al , 1989Jones et al 1987). Osborne et al (1987) found that neither TCDD nor tetrachlorodibenzofuran altered thyroid hormone binding to nuclear thyroid hormone receptors.…”